Research Collaboration & License, Development

Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





AMENDMENT NO. 2 TO RESEARCH, COLLABORATION

AND LICENSE/DEVELOPMENT AGREEMENT

BETWEEN TULARIK INC. AND

TAISHO PHARMACEUTICAL CO., LTD.



THIS AMENDMENT NO. 2 (this "Amendment") to the Research, Collaboration and License/Development Agreement dated as of March 20, 1996 (the "Collaboration Agreement") by and between Tularik Inc., a Delaware corporation with its principal office at Two Corporate Drive, South San Francisco, California 94080 (herein, together with its successors and assigns, "Tularik"), and Taisho Pharmaceutical Co., Ltd., a Japanese corporation with its principal office at 24-1, Takata 3-chome, T oshima-ku, Tokyo 171-8633, Japan (herein, "Taisho"), is entered into as of January 1, 1999;



W I T N E S S E T H:



WHEREAS, the parties previously entered into the Collaboration Agreement which, inter alia, (i) established a cooperative research and development

----- ---- relationship in order to discover, develop and market novel products whose action is based upon the regulation of Signal Transducers and Activators of Transcription ("STATs") involved in [ * ] functi ons; and (ii) set forth the terms of licenses to products that resulted from such cooperative research and development relationship;



WHEREAS, Tularik and Taisho desire to add and include their cooperative research relationship to develop and market novel therapeutic products whose action is based upon the regulation of STATs involved in [ * ] function, as well;



WHEREAS, in order to accomplish the foregoing, the parties have agreed to amend the Collaboration Agreement in part;



NOW, THEREFOR E, in consideration of the premises and the mutual covenants and agreements expressed herein, and for other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, and intending to be legally bound, Tularik and Taisho agree as follows:



1. Section 1.3 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



"Compound" shall mean (i) a substance which is identified by Tularik or Taisho during the term of the Research Program as either inhibiting or promoting the activity of STATs activated by [ * ]; and (ii) any such substance identified by Tularik within [ * ] after the end of the Research Program if [ * ].

2. Section 2.1 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



The parties agree to conduct a collaborative Research Program for identification and development of Compounds intended for use as Drug Candidates, to be conducted by both parties under the direction of the Research Committee. The Research Program shall consist primarily of [ * ] to identify specific Compounds with promising activity for regulation of STAT proteins activated by [ * ] using Tularik Assays and other technology available to the parties and (ii) each party endeavo r ing to work together to fulfill their respective obligations under Section 2.4 below to develop Compounds through application of medicinal chemistry and preclinical testing for commercialization of Products. For any given year of the Research Program, th e Research Program will be conducted in accordance with an annual research plan to be approved by the parties no later than [ * ] prior to the start of such year, upon recommendation of the Research Committee pursuant to Section 2.2(c)(1). The initial Ann u al Research Plan, for the year commencing on the Effective Date and ending on the day before the first anniversary of the Effective Date, is attached hereto as Exhibit C. Each Annual Research Plan may be revised by mutual consent of the parties from time to time.



3. Section 2.5 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



Program Funding. To support Tularik's activities in the Research Program, Taisho has paid Tularik [ * ] and agrees to pay Tularik, [ * ].



4. Section 2.6 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



Termination of Research Program. Upon not later than [ * ] prior notice Taisho may terminate the Research Program at the end of the fifth (5th) yea r of the Research Program if it shall be dissatisfied, in its sole judgment, with the progress or results of the Research Program. The Research Committee may terminate the Research Program any time if it determines the Research Program is no longer scient ifically useful. In case of such an early termination by Taisho or the Research Committee, Taisho shall be exempt from any payment(s) that would have become due and payable after such early termination date.



5. Section 2.8 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



During the conduct of the Research Program, Taisho and Tularik agree that they shall collaborate on an exclusive basis hereunder with respect to the identification, using the Tularik Assays, of Co mpounds for use in the Field in the Taisho Territory. This Section 2.8 shall not restrict either party's rights to [ * ].



6. Section 3.9 of the Collaboration Agreement is hereby amended to read in its entirety as follows:





[ * ] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





(a) Taisho shall pay Tularik within [ * ] after the occurrence of

the following events:



[ * ].



(b) Taisho shall pay Tularik within [ * ] after the occurrence of

the following events:



[ * ]



7. Exhibit B to the Collaboration Agreement is hereby amended to read in its entirety as follows:



[ * ]



[ * ]



[ * ]



[ * ]



[ * ]



8. Capitalized terms used herein but not otherwise defined herein shall have the respective meanings assigned to such terms in the Collaboration Agreement.



9. Except as expressly modified by this Amendment, all of the terms and conditions of the Collaboration Agreement and Amendment No. 1 to the Collaboration Agreement shall remain in full force and effect.



10. This Amendment may be executed in two counterparts, each of which shall be deemed an original but all of which shall be considered one and the same instrument.





[ * ] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





IN WITNESS WHEREOF, the parties have executed, or caused their duly authorized officer or representative to execute, this Amendment as of the day and year first above written.



TULARIK INC.



By: /s/ David V. Goeddel

------------------------------------ Name: David V. Goeddel Title: Chief Executive Officer





TAISHO PHARMACEUTICAL CO., LTD.



By: /s/ Kunihiro Kitamura

------------------------------------ Name: Kunihiro Kitamura, Ph.D. Title: General Manager

Research Strategy and Planning Section

Medicinal Research Group





[ * ] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





AMENDMENT NO. 1 TO RESEARCH, COLLABORATION

------------------------------------------

AND LICENSE/DEVELOPMENT AGREEMENT

---------------------------------

BETWEEN TULARIK INC. AND

------------------------

TAISHO PHARMACEUTICAL CO., LTD.

-------------------------------



THIS AMENDMENT NO. 1 (this "Amendment") to the Research, Collaboration an d License/Development Agreement dated as of March 20, 1996 (the "Collaboration Agreement") by and between Tularik Inc., a Delaware corporation with its principal office at Two Corporate Drive, South San Francisco, California 94080 (herein, together with i ts successors and assigns, "Tularik"), and Taisho Pharmaceutical Co., Ltd., a Japanese corporation with its principal office at 24-1, Takata 3-chome, Toshima-ku, Tokyo 171-0033, Japan (herein, "Taisho"), is entered into as of January 1, 1998;



W I T N E S S E T H:



WHEREAS, the parties previously entered into the Collaboration Agreement which, inter alia, (i) established a cooperative research and development relationship - ----- ---- in order to discover, develop and market nove l products whose action is based upon the regulation of Signal Transducers and Activators of Transcription ("STATs") involved in [ * ]; and (ii) set forth the terms of licenses to products that resulted from such cooperative research and development relat ionship;



WHEREAS, Tularik and Taisho desire to continue their cooperative research relationship to develop and market novel therapeutic products based on compounds identified during such research as having immune regulatory properties;



WHEREAS, in order to accomplish the foregoing, the parties have agreed to amend the Collaboration Agreement in part;



NOW, THEREFORE, in consideration of the premises and the mutual covenants and agreements expressed herein, and for other good and valuable consideration, the receipt and sufficiency of which is hereby acknowledged, and intending to be legally bound, Tularik and Taisho agree as follows:



1. Section 1.3 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



"Compound" shall mean (i) a substance which is identified by Tularik or Taisho during the term of the Research Program as either inhibiting or promoting the activity of STATs activated by [ * ] and (ii) any such substance identified by Tularik within [ * ] after the end of the Research Program [ * ]



2. Section 1.11 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



"Program Know-How" shall mean all tangible or intangible know-how, trade secrets, inventions (wheth er or not patentable), data, clinical and preclinical results, information, and any physical, chemical or biological material, including cell lines, any replication or any part of such material, all





[ * ] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





of which is in any way derived from or developed pursuant to activities du ring the course of the Research Program. Program Know-How shall not include any know-how, trade secrets, invention, data, information or material first developed, reduced to practice or discovered, each after any termination of the Research Program prior to the completion of the full six (6) year term.



3. Section 1.14 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



"Research Program" shall mean the collaborative program of six (6) years, which consists of six on e (1)-year periods, of research relating to the discovery and development of one or more Compounds, as such program is defined on Exhibit A and as the same may be further defined, revised and implemented, from time to time, by the parties on the recommend ation of the Research Committee, and as further described in Article 2.



4. Section 2.5 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



Program Funding. To support Tularik's activities in the Research Program, Taisho has paid Tularik [ * ] and agrees to pay Tularik, [ * ].



5. Section 2.6 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



Termination of Research Program. Upon not later than [ * ] prior notice Taisho may te rminate the Research Program at the end of the fourth (4/th/) or the fifth (5/th/) year of the Research Program if it shall be dissatisfied, in its sole judgment, with the progress or results of the Research Program. The Research Committee may terminate t h e Research Program any time if it determines the Research Program is no longer scientifically useful. In case of such an early termination by Taisho or the Research Committee, Taisho shall be exempt from any payment(s) that would have become due and payab le after such early termination date.



6. Section 7.1 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



Term. This Agreement shall expire on the later of (i) the expiration date of the last to expire patent licensed from Taisho to Tularik pursuant to Section 3.3(a) and (ii) the expiration date of the last to expire royalty obligation contained herein. Notwi thstanding the foregoing, if the Research Program is terminated prior to the completion of its full six (6) year term, this Agreement shall terminate upon the date on which the Research Program is terminated.



7. Section 7.2 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



Extensions. The parties may extend the term of this Agreement or of the Research Program on the written agreement of the parties. If the Research Program expires after the full six (6) year term thereof, Taisho and Tularik shall mutually determine whether this Agreement should survive or





[ * ] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





terminate following such expiration based upon an evaluation of the promise of Compounds identified during such term.



8. Section 12.3 of the Collaboration Agreement is hereby amended to read in its entirety as follows:



Notices. Any notice or other communication required or permitted to be given to either party hereto shall be in writing and shall be deemed to have been properly given and to be effective on the date of del ivery if delivered in person or by facsimile or five (5) days after mailing by registered or certified mail, postage paid, to the other party at the following address:



In the case of Tularik: Tularik Inc.

Two Corporate Drive

S. San Francisco, CA 94080

Fax: (650) 829-4303

Attention: Chief Executive Officer



In the case of Taisho:

Taisho Pharmaceutical Co., Ltd.,

24-1, Takata 3-chome

Toshimaku, Tokyo, 171-0033 Japan

Attention: Executive Vice President



9. Capitalized terms used herein but not otherwise defined herein shall have the respective meanings assigned to such terms in the Collaboration Agreement.



10. Except as expressly modified by this Amendment, all of the terms and conditions of the Collaboration Agreement shall remain in full force and effect.



11. This Amendment may be executed in two counterparts, each of which shall be deemed an original but all of which shall be considered one and the same instrument.





[ * ] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





IN WITNESS WHEREOF, the parties have executed, or caused their duly authorized officer or representative to execute, this Amendment as of the day and year first above written.



TULARIK INC.



By: /s/ David V. Goeddel

----------------------------------------- Name: David V. Goeddel Title: Chief Executive Officer





TAISHO PHARMACEUTICAL CO., LTD.



By: /s/ Kunihiro Kitamura

----------------------------------------- Name: Kunihiro Kitamura Title: General Manager, Research Strategy and Planning Section,

Medicinal Research Group





[ * ] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





RESEARCH, COLLABORATION





LICENSE/DEVELOPMENT







TULARIK INC.





TAISHO PHARMACEUTICAL CO., LTD.





RESEARCH, COLLABORATION





LICENSE/DEVELOPMENT AGREEMENT







[*] = Certain confidential information contained in this document, marked by brackets, is filed with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.

TABLE OF CONTENTS



Page

Article 1. Definitions............................................................ 1

1.1 "Agreement"........................................................... 1

1.2 "Annual Research Plan"................................................ 1

1.3 "Compound"............................................................ 1

1.4 "Confidential Information"............................................ 2

1.5 "Drug Candidate"...................................................... 2

1.6 "Field"............................................................... 2

1.7 "MHW"................................................................. 2

1.8 "NDA"................................................................. 2

1.9 "Net Sales"........................................................... 2

1.10 "Product"............................................................. 2

1.11 "Program Know-How".................................................... 2

1.12 "Program Patents"..................................................... 3

1.13 "Research Committee".................................................. 3

1.14 "Research Program".................................................... 3

1.15 "Taisho Compound Library"............................................. 3

1.16 "Taisho Know-How"..................................................... 3

1.17 "Taisho Licensed Technology".......................................... 3

1.18 "Taisho Patents"...................................................... 3

1.19 "Taisho Territory".................................................... 4

1.20 "Tularik Assays"...................................................... 4

1.21 "Tularik Compound Library"............................................ 4

1.22 "Tularik Know-How".................................................... 4

1.23 "Tularik Licensed Technology"......................................... 4

1.24 "Tularik Patents"..................................................... 4

1.25 "Tularik Territory"................................................... 5



Article 2. Research Program....................................................... 5

2.1 Objectives; Annual Research Plan...................................... 5

2.2 Research Committee.................................................... 6

2.3 Use of Taisho Compound Library........................................ 6

2.4 Research Diligence.................................................... 7

2.5 Program Funding....................................................... 7

2.6 Termination of Research Program....................................... 7

2.7 Right to Conduct Research............................................. 7

2.8 Exclusive Research Collaboration...................................... 7



Article 3. Development; Intellectual Property Rights; Payment Obligations......... 7

3.1 Development........................................................... 7

3.2 License to Taisho of Tularik Licensed Technology...................... 8

3.3 License to Tularik of Taisho Licensed Technology...................... 8

3.4 Sublicenses........................................................... 8



[*] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





TABLE OF CONTENTS



Page

3.5 Use Limitation of Compound Libraries.................................. 8

3.6 Nonuse of the Other Party's Technology Outside of the Field........... 9

3.7 Use of a Party's Own Substances....................................... 9

3.8 Development and Commercialization Diligence........................... 9

3.9 Benchmark Payments.................................................... 10

3.10 Royalties............................................................. 10

3.11 Payment; Reports...................................................... 11

3.12 Exchange Rate; Manner and Place of Payment............................ 11

3.13 Records and Audit..................................................... 11

3.14 Withholding of Taxes.................................................. 12

3.15 Reciprocal Arrangements with Third Parties............................ 12

3.16 Exclusive Development and Commercialization Collaboration............. 13



Article 4. Publication............................................................ 13



Article 5. Confidentiality........................................................ 13

5.1 Confidential Information; Exceptions.................................. 13

5.2 Financial Terms....................................................... 14



Article 6. Patents And Patent Applications........................................ 14

6.1 Ownership............................................................. 14

6.2 Patents............................................................... 15

6.3 Assignments........................................................... 16

6.4 No Representation..................................................... 16

6.5 Infringement of Patents by Third Parties.............................. 16

6.6 Infringement of Third Party Rights.................................... 18



Article 7. Term And Termination Of Agreement...................................... 19

7.1 Term.................................................................. 19

7.2 Extensions............................................................ 19

7.3 Termination for Material Breach....................................... 19

7.4 Insolvency or Bankruptcy.............................................. 19

7.5 Accrued Rights, Surviving Obligations................................. 19



Article 8. Indemnity.............................................................. 20

8.1 Product Liability Indemnity by Taisho................................. 20

8.2 Product Liability Indemnity by Tularik................................ 20



Article 9. Representations And Warranties......................................... 20

9.1 Taisho Representations, Warranties and Indemnities.................... 20

9.2 Tularik Representations, Warranties and Indemnities................... 21



Article 10. Import And Export Controls............................................ 22



[*] = Certain confidential information contained in this document, marked by brackets, has been omitted and filed separately with the Securities and Exchange Commission pursuant to Rule 406 of the Securities Act of 1933, as amended.





TABLE OF CONTENTS



Page

10.1 United States Laws.................................................... 22

10.2 Non-United States Laws................................................ 23



Article 11. Limitations Of Liability.............................................. 23



Article 12. Miscellaneous Provisions.............................................. 23

12.1 Waiver................................................................ 23

12.2 Assignment............................................................ 23

12.3 Notices............................................................... 23

12.4 Headings.............................................................. 24

12.5 Amendment............................................................. 24

12.6 Construction of Agreement and Choice of Law, Jurisdiction and Venue... 24

12.7 Force Majeure................................. ...